The Molecular Basis of Syndromic Retinitis Pigmentosa

描述（由申请人提供）：本项目的总体目标是描述一种称为泛酸激酶相关神经变性（PKAN，以前称为Hallervorden-Spatz综合征）的综合征性色素性视网膜炎的分子发病机制，其特征为异常视网膜电图、视网膜色素上皮中的脂褐素积聚和早期快速进行性色素性视网膜病变。这种常染色体隐性遗传疾病包括锥体外系功能障碍和基底神经节铁蓄积。PKAN是由PANK 2突变引起的，PANK 2是编码辅酶A（CoA）生物合成中关键调节酶（称为泛酸激酶）的四种人类基因之一。由于PANK 2是唯一与线粒体，我们假设，缺陷导致CoA缺乏症，能量和脂质代谢异常，氧化损伤和细胞凋亡的易感组织。我们建议研究PANK 2缺陷如何导致视网膜和神经元变性。 我们的具体目标是：1）创建代表疾病严重程度谱的Pank 2缺陷型小鼠突变体并描绘其相关表型; 2）鉴定体内和体外泛酸激酶2缺陷的代谢和分子扰动;和3）确定PANK 2突变是否与年龄相关性黄斑变性或特发性色素性视网膜病变相关。 关于PKAN的遗传基础的知识使得能够描绘临床可识别的疾病，以及开发分子诊断测试和合理治疗的新思路。这一发现将先前未被怀疑的代谢途径与视网膜病变和神经变性联系起来，并阐明了该途径中的缺陷在与PKAN共享病理特征的相关、更常见的疾病中的可能作用，包括年龄相关性黄斑变性、色素性视网膜炎和帕金森病。

DESCRIPTION (provided by applicant): The overall goal of this project is to delineate the molecular pathogenesis of a form of syndromic retinitis pigmentosa called pantothenate kinase-associated neurodegeneration (PKAN, formerly Hallervorden-Spatz syndrome) and characterized by abnormal electroretinogram, lipofuscin accumulation in the retinal pigment epithelium, and early, rapidly progressive pigmentary retinopathy. This autosomal recessive disorder includes extrapyramidal dysfunction and iron accumulation in the basal ganglia. PKAN is caused by mutations in PANK2, one of four human genes to encode a key regulatory enzyme in coenzyme A (CoA) biosynthesis, called pantothenate kinase. Since PANK2 is uniquely associated with mitochondria, we hypothesize that defects lead to CoA deficiency, energy and lipid metabolic abnormalities, oxidative damage and apoptosis in susceptible tissues. We propose to investigate how PANK2 defects cause retinal and neuronal degeneration. Our specific aims are: 1) to create Pank2 defective mouse mutants representing a spectrum of disease severity and delineate their associated phenotypes; 2) to identify metabolic and molecular perturbations in pantothenate kinase 2 deficiency in vivo and in vitro; and 3) to determine whether mutations in PANK2 are associated with age-related macular degeneration or idiopathic pigmentary retinopathy. Knowledge about the genetic basis of PKAN has enabled delineation of a clinically recognizable disease, as well as the development of a molecular diagnostic test and new ideas for rational therapies. This discovery has linked a previously unsuspected metabolic pathway with retinopathy and neurodegeneration and has illuminated a possible role for defects in this pathway in related, more common disorders that share pathologic features with PKAN, including age-related macular degeneration, retinitis pigmentosa and Parkinson disease.